Hereditary non-syndromic hearing loss affects 1:500 newborns and age related hearing loss afflicts the majority of the elderly population. In most forms of hearing loss, hair cell (HC) degeneration is a common final pathway. The long-term goal of our research is to decipher the cell type-specific transcriptional and signaling cascades that are necessary for inner ear development, and to apply this knowledge to identify: (a) genes necessary for hearing; and (b) potent regulators of differentiation, which could ultimately be used to restore hearing. ATOH1 is a master regulator of HC-fate that likely functions through the activation of a series of transcription factors (TFs) as well as non-regulatory genes. However, forced expression of ATOH1 in deafened ears is not sufficient to generate mature auditory HCs. Therefore, there is a critical need to identify the signaling cascades mediating the differentiatio of newly formed HCs. In this proposal we focus on the GFI1 and RFX TFs, whose orthologs in Drosophila are immediate targets of the ATOH1 ortholog. We recently identified an evolutionarily conserved role for the ciliogenic RFX proteins in regulating the newborn mouse HC-specific transcriptome, and identified Rfx3 and Rfx7 as the most abundant Rfx transcripts in HCs.
In Specific Aim 1 we will determine the role of RFX in HC differentiation using conditional knockout mice, and identify and validate the RFX-regulated target genes in HCs.
In Specific Aim 2 we will identify the molecular targets of GFI1, a gene necessary for outer HC survival and vestibular HC differentiation, and validate the roles of newly identified targets in vivo. In orderto facilitate dissemination of data generated in this and other proposals in the public domain, and as a step towards building the transcriptional networks necessary for inner ear cell type-specific differentiation, we will build and maintain the gEAR - a gene Expression for Auditory Research portal.

Public Health Relevance

This work will decipher the principal gene regulatory networks involved in hair cell differentiation and survival, a critical step towards the development of therapies for the treatment and/or prevention of hearing loss. From an immediate translational standpoint, these transcriptional targets and cell type-enriched transcripts will be used to help prioritize gene variants for deafness, identified by exome sequencing. In addition, our novel cell type-specific gene expression portal for auditory research (gEAR) will facilitate data sharing and dissemination amongst researchers in the field, thereby promoting hearing-related research, facilitating characterization of transcriptional networks and discovery of genes necessary for hearing.

Agency
National Institute of Health (NIH)
Institute
National Institute on Deafness and Other Communication Disorders (NIDCD)
Type
Research Project (R01)
Project #
5R01DC013817-05
Application #
9654735
Study Section
Auditory System Study Section (AUD)
Program Officer
Freeman, Nancy
Project Start
2015-03-01
Project End
2020-02-29
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
5
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Otolaryngology
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Matern, Maggie; Vijayakumar, Sarath; Margulies, Zachary et al. (2017) Gfi1Cre mice have early onset progressive hearing loss and induce recombination in numerous inner ear non-hair cells. Sci Rep 7:42079
Elkon, Ran; Milon, Beatrice; Morrison, Laura et al. (2015) RFX transcription factors are essential for hearing in mice. Nat Commun 6:8549